Discrete elements for 3D microfluidics

ABSTRACT

A module may be provided with at least one opening, the opening being an endpoint of a microfluidic channel that passes through at least part of the module. A set of multiple such modules may be arranged into an arrangement of modules, which may be coupled together using one or more coupling mechanisms included on each module. The arrangement of modules may fit within a regular polyhedral grid, and each module within the arrangement of modules may have a form suitable for arrangement of the modules within the regular polyhedral grid. Fluid may then flow through at least a subset of the arrangement of modules via the microfluidic channel of each module of the subset of the arrangement of modules. Some modules may include sensors, actuators, or inner microfluidic channel surface coatings. The arrangement of modules may form a microfluidic circuit that can perform a microfluidic circuit function.

CROSS-REFERENCE TO RELATED APPLICATION

This application is based upon and claims priority to U.S. provisionalpatent application 62/010,107, entitled “Discrete MicrofluidicComponents for Modular Three-Dimensional Circuits,” filed Jun. 10, 2014.The entire content of this application is incorporated herein byreference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under Grant No.1R01GM093279 awarded by National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND

Technical Field

This disclosure relates to microfluidic circuits and to techniques forconstructing them.

Description of Related Art

Microfluidic technology typically includes devices that can manage andmove amounts of fluid on a scale of nano-liters or smaller. Typically,microfluidic devices have channels for transferring fluids where theReynolds number is less than 100 and often times lower than 1. In thisregime of Reynolds numbers, the flow may be laminar. Systems of thisnature are rapidly becoming desirable tools for a variety ofapplications, including high-precision materials synthesis, biochemicalsample preparation, and biophysical analysis. Microfluidic devices arecommonly fabricated in monolithic form by means of microfabrication.This can limit device construction to a planar geometry, which can befunctionally limiting and expensive.

Modular microfluidic platforms have been conceived, but are all limitedto 2-dimensional platforms, and do not allow for allow for deviceassembly in 3-dimensions. Furthermore, other modular microfluidicplatforms are generally limited in scope (e.g., may only createmicrofluidic flow paths with little other functionality), areprohibitively expensive, are difficult to use, or use nonstantadizedfootprints, models, or connectors/ports. Some may only produce veryspecific types of structures (e.g., mixers). Further still, othermodular microfluidic platforms do not allow for facile integration ofsensors or actuators into their components, which further limits thescope of device applications.

Therefore, an improved modular microfluidic platform is needed.

SUMMARY OF THE CLAIMED INVENTION

A first system for fluid handling is described. The first systemincludes a first opening on a first module. The first system alsoincludes a microfluidic channel passing through at least part of thefirst module. The microfluidic channel has at least one endpoint at thefirst opening. The microfluidic channel allows fluid flow. The firstsystem also includes a first coupling mechanism allowing fluid flowbetween the first opening and a second module.

A second system for fluid handling is described. The second systemincludes a plurality of modules. Each module of the plurality of modulesincludes at least one opening that serves as an endpoint of amicrofluidic channel allowing for fluid flow and passing through atleast part of the module. The plurality of modules may be arranged intoan arrangement of modules that fits within a regular polyhedral grid.Fluid may flow through at least a subset of the plurality of modules viathe microfluidic channel of each module of the subset of the pluralityof modules.

A method for fluid handling is described. The method includes receivinga fluid at a first opening of a first module, the first opening coupledto a second module, the second module including a second microfluidicchannel. The method also includes passing the fluid through amicrofluidic channel that passes through the first module from the firstopening to a second opening. The method also includes transmitting thefluid through the second opening, the second opening coupled to a thirdmodule, the third module including a third microfluidic channel.

BRIEF DESCRIPTION OF DRAWINGS

The drawings are of illustrative embodiments. They do not illustrate allembodiments. Other embodiments may be used in addition or instead.Details that may be apparent or unnecessary may be omitted to save spaceor for more effective illustration. Some embodiments may be practicedwith additional modules or steps and/or without all of the modules orsteps that are illustrated. When the same numeral appears in differentdrawings, it refers to the same or like modules or steps.

FIG. 1A illustrates a perspective view of a single exemplary module witha single exemplary connector coupled to the module.

FIG. 1B illustrates a perspective view of three exemplary modulescoupled together in a three-module arrangement in the shape of a line.

FIG. 2A illustrates a front view of a male coupling pin of a connector.

FIG. 2B illustrates a perspective view of a connector.

FIG. 3 illustrates an example library of different microfluidicelements, including the connector and different types of modules.

FIG. 4A illustrates an exemplary 2-input, 1-output concentrationgradient generator device in which a single branch resistor varies themixing ratio.

FIG. 4B illustrates the exemplary 2-input, 1-output concentrationgradient generator device of FIG. 4A in symbolic circuit notation.

FIG. 5 is a graph comparing a mixing ratio to a ratio of resistances atthe two branches of the gradient generator device of FIG. 4A and FIG. 4Bthat includes model data as well as experimental data, and illustrates adark-colored fluid mixing with a light-colored fluid at variousexperimental points on the graph.

FIG. 6A illustrates an example of two single-outlet subcircuits combinedto parallelize operation of a tunable mixer to yield a two-outletdevice.

FIG. 6B illustrates an example of three single-outlet subcircuitscombined to parallelize operation of a tunable mixer to yield athree-outlet device.

FIG. 6C illustrates an example of four single-outlet subcircuitscombined to parallelize operation of a tunable mixer to yield afour-outlet device.

FIG. 7A illustrates the two-outlet device of FIG. 6A in symbolic circuitnotation.

FIG. 7B illustrates the two-outlet device of FIG. 6B in symbolic circuitnotation.

FIG. 7C illustrates the two-outlet device of FIG. 6C in symbolic circuitnotation.

FIG. 8 illustrates an exemplary T-junction emulsification circuit.

FIG. 9 illustrates an example of four-outlet T-junction emulsificationcircuit.

FIG. 10 illustrates an example of a flow-focus configurationemulsification circuit.

FIG. 11A illustrates an example of droplet length measurements, measuredalong the center axis of exit tubing, for the T-junction emulsificationcircuit of FIG. 8.

FIG. 11B illustrates an example of droplet length measurements, measuredalong the center axis of exit tubing, for the flow-focus configurationemulsification circuit of FIG. 10.

FIG. 12A illustrates an example of a module with a straight pass channelintersecting the bream created between a discrete near infrared (NIR)diode emitter to a phototransistor receiver.

FIG. 12B illustrates an example of an assembly where the near infrared(NIR) sensing module of FIG. 12A is placed downstream from a T-junctionproducing droplets that absorb the near infrared (NIR) beam as theycross its path.

FIG. 12C illustrates an example of a periodical signal generated by theoutput of the phototransistor receiver in FIG. 12A.

FIG. 12D illustrates an example of droplet length measurementdistribution as determined by an near infrared (NIR) sensor and throughoptical measurements.

FIG. 13 illustrates an example of an electrical circuit diagramdepicting the operation of the near-infrared droplet measurementelement.

FIG. 14 illustrates an exemplary thermal sensing module where thechannel coming in from the top surface can house an off-the-shelfthermistor diode.

FIG. 15 illustrates an example of a magnet integrated into a module,which may be used in conjunction with micron scale paramagnetic beads.

FIG. 16 illustrates an example of a module with an integrated valveunit.

FIG. 17A illustrates an internal view of an exemplary optical sensormodule where an LED is housed on the top surface of the module and asensor is housed on the bottom surface of the module.

FIG. 17B illustrates an opaque external view of the exemplary opticalsensor module of FIG. 17A.

FIG. 18 illustrates an example of a mixer module with a visible openingon the front left side and a non-visible opening on the right-back side,and a visual indicator on the top surface.

FIG. 19 illustrates an example of a straight-pass module with twoopenings at the top and at the bottom, and with a visual indicatorpresent on several side surfaces of the module.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Illustrative embodiments are now described. Other embodiments may beused in addition or instead. Details that may be apparent or unnecessarymay be omitted to save space or for a more effective presentation. Someembodiments may be practiced with additional modules or steps and/orwithout all of the modules or steps that are described.

A microfluidic platform is described herein that includes modular,reconfigurable modules that contain fluidic and sensor elements that maybe configured into many different microfluidic circuits. This may allowfor application of network analysis techniques, like those used inclassical electronic circuit design, which may facilitate astraightforward design of predictable flow systems.

A module may be provided with at least one opening, the opening being anendpoint of a microfluidic channel that passes through at least part ofthe module. A set of multiple such modules may be arranged into anarrangement of modules, which may be coupled together using one or morecoupling mechanisms included on each module. The arrangement of modulesmay fit within a regular polyhedral grid, and each module within thearrangement of modules may have a form suitable for arrangement of themodules within the regular polyhedral grid. Fluid may then flow throughat least a subset of the arrangement of modules via the microfluidicchannel of each module of the subset of the arrangement of modules. Somemodules may include sensors, actuators, or inner microfluidic channelsurface coatings. The arrangement of modules may form a microfluidiccircuit that can perform a microfluidic circuit function.

A sample library of standardized modules and connectors can bemanufactured following this approach. Flow characteristics of themodules can be derived to facilitate the design and construction of atunable concentration gradient generator device with a scalable numberof parallel outputs. Systems can also be rapidly reconfigurable byconstructing variations of a microfluidic circuit for generatingmonodisperse microdroplets in two distinct size regimes and in a highthroughput mode by simple replacement of emulsifier sub-circuits. Activeprocess monitoring can be introduced in the system by constructing anoptical sensing element for detecting water droplets in a fluorocarbonstream.

By moving away from large-scale integration towards standardizeddiscrete elements, complex 3-D microfluidic circuits can be designed andassembled using approaches comparable to those used by the electronicsindustry.

The standardized footprint of modules allows for three dimensionallattice assemblies. A lattice can be defined as a regular periodic setof points in space associated with the tiling of a primitive cell. Herea primitive cell is constructed such that by definition it does notcontain a lattice point other than at its corners. A module like that ofwhich has been described may occupy an integer number of primitive cellsin the lattice. The shape of a module may be determined by one of moreprimitive cells. For example, in a cubic lattice, the modules may bearranged to be simply cubic or an integer number of primitive cubes inlength, width and height. More broadly, a lattice with a polyhedralprimitive cell may have an integer number of primitive polyhedrals.

FIG. 1A illustrates a perspective view of a single exemplary module witha single exemplary connector coupled to the module.

The exemplary module 100 of FIG. 1A is substantially cube-shaped. Inother cases, a module similar to the module 100 of FIG. 1A may becylindrical, spherical, or polyhedral (e.g., a cube, a rectangularprism, a polygonal prism, a polygonal pyramid, a tetrahedron, anoctahedron, a dodecahedron, an icosahedron, or any otherthree-dimensional shape that may be produced from an arrangement ofpolygons). While the size of each side of the module 100 of FIG. 1A issubstantially identical (e.g., a cube), a different module may be longerin one or more directions (e.g., a rectangular prism or an “L” or “T” or“X” or “plus symbol” shape).

The length of each side of the module 100 may be at a picometer scale(e.g., between 1 and 1000 picometers), at a nanometer scale (e.g.,between 1 and 1000 nanometers), at a micrometer scale (e.g., between 1and 1000 micrometers), at a millimeter scale (e.g., between 1 and 1000millimeters), at a centimeter scale (e.g., between 1 and 10centimeters). In some exemplary modules, at least one side of the module100 may be approximately 0.1 to 10 centimeters in length. In oneembodiment, at least one side of the module 100 may be approximately 1centimeter in length.

The module 100 includes a module-coupling opening 110, which may be anyshape. The module-coupling opening 110 of FIG. 1A is circular in shape,but it may be ovoid or polygonal (e.g., the module-coupling opening 110may be a square, a triangle, a rectangle, a pentagon, a hexagon, anoctagon, or any other polygonal shape).

The module-coupling opening 110 of the module 110 is located at a femalecoupling port 140 of the module 100. The female coupling port 140 is aninlet designed to accept a male coupling pin, and may include an elasticreversible seal (or other type of seal, o-ring, or gasket) to secure afit between the female coupling port 140 and male coupling pin. Forexample, the seal may use silicone, rubber, or plastic. The femalecoupling port 140 may also include an adhesive (e.g., glue) to keep amale coupling pin in place once inserted. The female coupling port 140of FIG. 1A is illustrated in a coupled state, where the female couplingport 140 of FIG. 1A is coupled with the bottom male coupling pin 135 ofthe connector 130.

The female coupling port 140 of FIG. 1A is in the shape of a rectangularprismic indentation into the center of the top face of the module 100,but may be another shape (e.g., a cylindrical indentation, a ovoidcylindrical indentation, a polygonal prismic indentation). Similarly,the bottom male coupling pin 135 and top male coupling pin 125 of theconnector 130 of FIG. 1A in the shape of a rectangular prismic extrusionfrom the circular bottom and top faces of the connector 130 but may beanother shape (e.g., a cylindrical extrusion, a ovoid cylindricalextrusion, a polygonal prismic extrusion).

The module 100 also includes an external port 115. The external port 115may be a port that allows fluid flow to and from an external device (notshown) that may attach to the module 100 using the external port 155.The external port 115 may be of a size that allows a standardized fluidtransfer interface with existing external devices. For example, theexternal port 115 may be designed to snugly fit widely availablepolyether ether ketone (PEEK) tubing (e.g., typically 1/16 inch outsidediameter, ⅛ inch outside diameter, 1.8 millimeter outside diameter) orcapillary PEEK tubing (e.g., typically 360 micrometer outside diameter,510 micrometer outside diameter, or 1/32 inch outside diameter) in orderto allow users to interface with their existing external devices withouthaving to commit to a proprietary chip-to-world interconnect solution.The channel 105 and/or module-coupling opening 110 may thus have asimilarly sized outside diameter as any of the sizes of PEEK orcapillary PEEK tubing described above. Alternately, the external port115 may include a proprietary fluid transfer port or connector.

The external port 115 may in some cases include a seal to bettermaintain a connection with an external device. Such a seal may be anelastic reversible seal (or other type of seal, o-ring, or gasket) tosecure a fit between the external port 115 and external device (e.g.,which may connect to the external port 115 through PEEK tubing). Forexample, the seal may use silicone, rubber, or plastic. The externalport 115 may also include an adhesive (e.g., glue) to keep an externaldevice or tubing in place once such a connection is made.

The external device may include, for example, pump, a reservoir, or asensor.

The module 100 of FIG. 1A includes a module channel 105 with oneendpoint at the module-coupling opening 110 and the other endpoint atthe external port 115. The module channel 105 is a microfluidic channelthat may transfer a fluid to and/or from the module-coupling opening110, and to and/or from the external port 115. The channel 105 may be acylindrical channel as illustrated in FIG. 1A, or may alternately be anyother three-dimensional shape that may be used for fluid transfer (e.g.,an ovoid cylindrical channel or a polygonal prism-shaped channel).

The module 100 of FIG. 1A is shown coupled to a connector 130. Theconnector 130 is an element with two male coupling pins that is designedto assist in coupling a first module to a second module (e.g., see thethree coupled modules of FIG. 1B). In particular, the connector 130includes a top male coupling pin 125 that is uncoupled and a bottom malecoupling pin 135 that is illustrated as coupled to the female couplingport 140 of the module 100. A seal may in some cases be included as partof each male coupling pin to better maintain a connection between themale coupling pin and a female coupling port. For example, such a sealmay be an elastic reversible seal (or other type of seal, o-ring, orgasket) to secure a fit between the male coupling pin 135 and femalecoupling port 140. For example, the seal may use silicone, rubber, orplastic. The male coupling pin 135 may also include an adhesive (e.g.,glue) to keep a male coupling pin 135 in place once inserted into thefemale coupling port 140.

The connector 130 includes a connector channel 150 that is illustratedas a square-prism-shaped tube in FIG. 1A (but may alternately be adifferent shape, such as a cylindrical tube or polygonal prismic tube).The connector channel 150 allows fluid flow between the connector topopening 145 at the end of the top male coupling pin 125 and themodule-coupling opening 110 at the surface of the female coupling port140 of the module 100 (coupled to the end of the bottom male couplingpin 135). The square prism shape of the male coupling pins and connectorchannel 150 may be used for optical clarity (e.g., quick differentiationof interfaces) and to ensure consistent cross-sectional channelorientation between the channel 105 and connector channel 150.

While the connector channel 150 is illustrated using a different shape(e.g., a square prism shaped tube) as the shape of the channel 105(e.g., a cylindrical tube), it should be understood that this shapedifferent is exemplary rather than limiting. The connector channel 150and channel 105 may be the same shape in some cases.

The connector 130 of FIG. 1A also includes a spacer 153, which iscylindrical as illustrated in FIG. 1A (but may alternately be adifferent shape, such as a polygonal prism or a sphere). The spacer 153is optional (e.g., the connector 130 may simply be two male couplingmodules 125 and 135 back-to-back). If the spacer 153 is included as partof the connector 130, it may be transparent or translucent and behave asa lens that optically magnifies the appearance of fluid flowing throughthe connector channel 150 to aid in post-assembly test and inspection.The spacer 153 may also assist in more easily putting together multiplemodules (e.g., by making the connector 130 larger and easier to grasp)and more easily viewing separate modules once multiple modules arecoupled together (e.g., by spacing the modules farther apart andallowing viewing of the fluid flow via the lens functionality of thespacer 153).

A second module (not shown) may couple to the connector 130 at theconnector top male coupling pin 125 (e.g., at a female coupling port ofthe second module). The module 100 may thus be coupled to a secondmodule (not shown).

The first module 100 may alternately be coupled to a second module (notshown) without the connector 130 if the second module (not shown)includes a male coupling pin oriented similarly to the bottom malecoupling pin 135 of FIG. 1A.

Another module may include, in place of the external port 115 of themodule 100, a second module-coupling opening with a second femalecoupling port similar to the module-coupling opening 110 and femalecoupling port 140 (e.g., see central module 170 of FIG. 1B). This mayallow such a module to be coupled to two different modules on eitherend. Yet other modules may include one or more additionalmodule-connecting openings and corresponding female coupling ports(e.g., see the various types of modules. Yet other modules may includeadditional external ports similar to external port 115. Some modules mayinclude multiple module-connecting openings and corresponding femalecoupling ports on a single face. Some modules may include multipleexternal ports on a single face.

Some modules may include various mechanisms, such as sensors (thermalsensor, a chemical sensor, an optical sensor, an electrical sensor, amechanical sensor, a magnetic sensor), mixer modules (e.g., which mayinclude helical or winding channels in order to aid the mixing of twofluids), resistors (e.g., that slow the flow of a fluid the higher theresistance of the resistor, for example using channels that arelengthened using turning or winding or helical paths, channels that arenarrowed, or channels that are partially occluded such as through aporous solid placed within the channel), actuators (e.g., poweringvalves, magnets pumps, or reservoirs). Various types of exemplarymodules are listed in FIG. 3.

Methods of fabrication of the module 100 may utilizePolydimethylsiloxane (PDMS) or Poly(methyl methacrylate) (PMMA) by lostwax casting. Other materials that may be used through additivemanufacturing techniques may include but are not limited to acrylates,acrylonitrile butadiene styrene (ABS) plastic, polylactic acid (PLA),polycarbonates, polypropylenes, polystyrenes, other polymers, steel,stainless steel, titanium, gold, and silver.

One or more exterior faces of each module 100 may be marked or embeddedwith symbolic visual indicators 120 that point out the orientationand/or type of element. This may aid in rapid assembly based ondiagrammatic expression of the intended system. These may be similar toorientation marks on the packaging of fundamental discrete electroniccomponents, such as resistors, capacitors, inductors, and diodes. Forexample, the visual indicators 120 of FIG. 1A indicate that the module100 includes a module-coupling opening 110 and a external port 115. Thevisual indicator 120 of FIG. 1A is a shape similar to a “T” that isengraved into each side surface of the module 100, with the long centralpillar of the “T” shape aligned with the channel 105 and endig at themodule-coupling opening 110, and the perpendicular endpiece of the “T”shape corresponding to the face of the module 100 that includes theexternal port 115. The visual indicator 120 may be one or more exteriorsurfaces of a module 100 (e.g., in FIG. 1A, the four exterior surfacesnot including the module-coupling opening 110 and the closed endpoint115). A visual indicator 120 may include an engraved shape (e.g., as inFIG. 1A), an embossed shape, an engraved alphanumeric string, anembossed alphanumeric string, a printed image, a printed alphanumericstring, a printed barcode, an engraved barcode, an embossed barcode, orsome combination thereof. Various types of exemplary modules andexemplary corresponding visual identifiers are listed in FIG. 3.

The top male coupling pin 125 of the connector 130 may then be used tocouple or affix a second module (not shown) to the first module. Inparticular, a female coupling port (not shown) of the second module (notshown) may couple with the top male coupling pin 125 of the connector130. The bottom male coupling pin 135 of the connector 130 may thencouple with the female coupling port 140 of the first module 100 asillustrated in FIG. 1A, thus coupling the first module 100 with thesecond module (not shown).

In an alternate embodiment, the connector 130 may be permanently coupledto the module 100 (e.g., the bottom male coupling pin 135 of theconnector 130 and the female coupling port 140 of the module 100 arefused together, adhesively attached, or manufactured without anyseparation).

In another alternate embodiment, the module 100 may include a malecoupling pin in place of the female coupling port 140, while theconnector 130 may include two female coupling ports in place of the topmale coupling pin 125 and bottom male coupling pin 135.

Module and Connector Design

FIG. 1B illustrates a perspective view of three exemplary modulescoupled together in a three-module arrangement in the shape of a line.

The three-module arrangement 155 of FIG. 1B includes, from left toright, a leftmost module with one opening 160, a connector 165, acentral module with two openings, a connector 175, and a rightmostmodule with one opening 180.

The connector 165 and connector 175 may be separate male-to-maleconnectors as illustrated in FIG. 1A. If this is the case, the leftmostmodule 160 then includes a single female coupling port on its rightmostface, the rightmost module 180 includes a single female coupling port onits leftmost face, and the central module 170 includes a first femalecoupling port on its leftmost face and a second female coupling port onits rightmost face. The connector 165 connects the leftmost module 160to the central module 170, and the connector 175 connects the centralmodule 170 to the rightmost module 180.

Keeping the module-based coupling mechanisms female and the spacer-basedcoupling mechanisms male allows for consistency in joinder operationsbetween different modules. In an alternate embodiment, the module 160,module 170, and module 180 may include male coupling pins, while theconnector 165 and connector 175 may each include two female couplingports. Consistency in joinder operations between different modules ismaintained using this coupling method. In yet another alternateembodiment, the modules of FIG. 1B may have a mixture of male and femalecoupling ports, and the spacers of FIG. 1B may then also have a mixtureof male and female coupling ports. Such an alternate embodiment maybreak consistency of joinder operations, but may be useful, for example,to suggest to a user that certain modules should be combined in aparticular order. Such a suggestion may also be accomplished bydifferently-shaped male coupling pins and corresponding female couplingports for modules that should be coupled together.

While the connector 165 and connector 175 may be separate elements fromthe modules of FIG. 1B, this need not be the case. In particular, eachof the connector 165 and the connector 175 may be permanently coupleddirectly to at least one of the modules of FIG. 1B as discussed as analternate embodiment of FIG. 1A. For example, connector 175 may becoupled to the rightmost module 180 and connector 165 may be coupled tothe central module 170. Alternatively, connector 175 may be coupled tothe central module 170 and connector 165 may be coupled to the leftmostmodule 160. Alternatively, connector 175 may be coupled to the rightmostmodule 180 and connector 165 may be coupled to the leftmost module 160.Alternatively, connector 175 and connector 165 may both be coupled tothe central module 170 (e.g., so that the central module 170 has twomale coupling pins 125).

FIG. 2A illustrates a front view of a male coupling pin of a connector.

The connector 130 of FIG. 2 includes a spacer 153 with a connector face220 (e.g., also a face of the spacer 153) and includes a male couplingpin 205 (e.g., the top male coupling pin 125 or bottom male coupling pin135) with square connector top opening 210 (e.g., connector top opening145) to a square-prism-shaped connector channel 150.

The channel opening 210 (and therefore channel 150) may be centered atthe top male coupling pin 205. The seating of the top male coupling pin205 within a female coupling port (not shown), which may be an inlet orport shaped like an inward rectangular prism, may ensure self-alignmentand continuity between channels, as illustrated in FIG. 1A between theconnector channel 150 and the module channel 105. Unlike jumper-cablestyle interconnects, coupling mechanisms of this style may suffer froman accumulation of particles or increase requirements for sample volumesby breaking circuit routing out of the microfluidic environment.

The connector channel 150 may have, for example, an approximately 1millimeter (mm) side length (or, e.g., a 1 mm diameter if the connectorchannel 150 was a circular prism and the connector top opening 210 acircle). Alternately, a different side length or diameter may be usedthat maintains a low Reynolds number.

The connector channel 150 may be larger than a module channel 105 (e.g.,module channel 105 of module 100 of FIG. 1A). For example, a modulechannel 105 may have a 500-750 micrometer side length (or diameter).This may limit the contribution of the connector channel 150 tohydrodynamic resistance, while ensuring low Reynolds number flow andmicroliter scale enclosed volumes, preserving the hallmark conditionsfor microfluidic flow. Tables 2 and 3 herein set forth examples.

FIG. 2B illustrates a perspective view of a connector. In particular,FIG. 2B illustrates a perspective view of the connector 130 of FIG. 1with opaque sides (e.g., the connector channel 150 is not visible) whileit is separate from the module 100.

FIG. 3 illustrates an example library of different microfluidicelements, including the connector and different types of modules. Theconnector 325 (e.g., the connector 130 of FIG. 1A, FIG. 2A, and FIG. 2B)may be used to couple the various different types of modules together.The modules include a straight pass 330, an L-joint 335, a mixer 340, aT-junction 345, an interface 355 (e.g., the module 100 of FIG. 1A is aninterface module 355), an XT-Junction 360, an XX-Junction 365).

Each module may have a corresponding visual indicator 310 that may beused to identify it, similarly to the “T” shaped visual indicator 120 ofmodule 100. Each module may also have a corresponding circuit symbol320. The circuit symbol 320 corresponding to each module associates theparticular module with a circuit symbol commonly used in electronics(e.g., resistors, power sources, ground). The various modules mayperform functions that allow arrangements of modules to behave similarlyto electronic circuits, with the circuit symbols 320 identified in FIG.3 being possible circuit symbols that may be used corresponding to eachidentified element.

The library of FIG. 3 is arranged in a table. The first (leftmost)column 305 names particular microfluidic elements 305. The second column310 identifies an exemplary visual indicator 310 that may be used toidentify each named element. The third column 315 illustrates anexemplary illustrated embodiment 315 of the identified element. Thefourth column 320 identifies a circuit symbol 320 that may correspond tothe particular module identified.

Each of the modules depicted in FIG. 3 may have different terminalhydrodynamic properties. Example terminal hydrodynamic properties ofthese example modules are given in the following Table 1:

TABLE 1 R R_(exp) Element h (μm) Label (MPa · s · m⁻³) (MPa · s · m⁻³)Connector 1000 R_(C,1000) 227.2  223.1 ± 5.5% 500 R_(SP,500) 2726.42720.41 ± 3.7%  Straight Pass 750 R_(SP,750) 538.55 525.69 ± 6.2% 1000R_(SP,1000) 170.4 169.67 ± 3.1% 500 R_(L,500) 2726.4 2720.41 ± 3.7% L-Joint 750 R_(L,750) 538.55 525.69 ± 6.2% 1000 R_(L,1000) 170.4 169.67± 3.1% 635 R_(M,635) 16227 17708.04 ± 4.2%  Mixer 750 R_(L,750) 6395.36218.5 ± 7.2% 1000 R_(L,1000) 1846 1838.1 ± 3.1% 500 R_((T),500) 1363.21360.21 ± 3.7%  T-Junction 750 R_((T),750) 269.28 262.85 ± 6.2% 1000R_((T),1000) 85.2 84.835 ± 3.1% 500 R_((X),500) 1363.2 1360.21 ± 3.7% X-Junction 750 R_((X),750) 269.28 262.85 ± 6.2% 1000 R_((X),1000) 85.284.835 ± 3.1% Interface 750 R_(I,750) 448.79 438.08 ± 6.2% XT-Junction750 R_((XT),750) 269.28 262.85 ± 6.2% XX-Junction 750 R_((XX),750)269.28 262.85 ± 6.2% IR Sensor 642.5 R_(IR,642.5) 999.95  993.57 ± 0.99%

Table 1 charts each element listed in FIG. 3 as well as an Infrared(“IR”) sensor. Table 1 includes a measurement “h”, which measures a sidelength of a channel (e.g., assuming a square-prism-shaped channel) ofthe microfluidic element (e.g., the module channel or the connectorchannel if the element is the connector) in micrometers (“μm”). Table 1gives each of these modules (at each channel side length) a label. Table1 then gives a calculated hydrodynamic resistance R of the element, inunits of Megapascal (MPa) seconds (s) per cubic meter (m^−3), as well asan experimentally observed hydrodynamic resistance R_(exp) in the sameunits.

The hydraulic resistance of each element was calculated for use incircuit analysis assuming low Reynolds number flow, and varied by eithermodulating the cross-sectional side length of the channel or the lengthof the channel segment packed into the module. Each element was designedusing straight channel segments with square cross-sections such that thenet resistance for geometrically complex two-port devices (e.g.helically shaped mixers) could be computed from the series addition ofinternal resistances. The resistances of segments themselves werecalculated using the following equation:

$R_{hyd} = \frac{28.4\;\eta\; L}{h^{4}}$

This equation was derived from the solution to the Navier-Stokesequation for Poiseuille Flow in straight channels. See Bruus, H.Theoretical Microfluidics. η is the dynamic viscosity of pure water atroom temperature (1 mPa s), L is the length of a channel segment, and his the height or width of the (square cross-section) channel.

In order to determine the approximate resistance of the modules to usein a further network analysis of assembled circuits, the averagecross-sectional side-length of several channels was optically measured,as reflected in the following Table 2, and the variation from designedvalues was determined:

TABLE 2 h (μm) h_(measured) (μm) n 1000 1001 ± 8  75 750  754 ± 12 100642.5 644 ± 2 12 635 621 ± 7 12 500 500 ± 5 36

In Table 1, the values “h” illustrate the side lengths of modules asintended, in micrometers. The values “h_(measured)” illustrate anaverage of side lengths of actually produced microfluidic elements. Thevalues “n” are a sample size of the number of experimental microfluidicelements produced at the given side lengths.

The expected resistance and tolerance (Table 1) for each elementassociated with these values was found to deviate within a rangecomparable to that of standard discrete electronic resistors. Forelements with more than two ports, an equivalent internal circuit modelwas constructed and the internal segment resistance is statedexplicitly. In elements with bends and corners, the resistance for eachstraight internal segment was added in series by assuming low-Reynoldsnumber (i.e. purely laminar) flow.

Tunable Mixing Through Flowrate Division

The accuracy of the element resistance calculations was gauged byconstructing a parallel circuit that compares disparate branch flowrates due to a constant pressure source.

FIG. 4A illustrates an exemplary 2-input, 1-output concentrationgradient generator device in which a single branch resistor varies themixing ratio. The single branch resistor is located on the right branchof the device and is labeled as R_(SELECT) 410 in FIG. 4A, and is amixer module 340. The left branch of the device instead includes astraight pass module 330 in the corresponding location, labeled R_(REF)405 (e.g., a “reference” resistance). The left branch is coupled via anexternal port 115 to a source B 440, while the right branch is coupledvia an external port 115 to a source Y 450. The two branches meet at aT-junction 460 when the fluid is pulled using a negative displacementpump 420 from the source B 440 and source 450 and eventually into thereservoir 430. An output resistance is measured after the T-junction 460as R_(OUTPUT) 415.

The negative displacement pump 420 may, for example, be a syringe pump.

FIG. 4B illustrates the exemplary 2-input, 1-output concentrationgradient generator device of FIG. 4A in symbolic circuit notation. Inparticular, R_(REF) 405, R_(SELECT) 410, R_(OUTPUT) 415 are depicted asresistors. Source B 440 (e.g., a reservoir filled with a first sourcefluid), Source Y 450 (e.g., a reservoir filled with a second sourcefluid), and Reservoir 430 (e.g., a reservoir to receive the resultingmixed output fluid) are depicted as ground elements. The negativedisplacement pump 420 is depicted as a power source. Fluid flow fromSource B 440 in the left branch is depicted as Q_(B) 445. Fluid flowfrom Source Y 450 in the right branch is depicted as Q_(Y) 455. Fluidflow after the T-junction 460 (e.g., in the output prong) is depicted asQ_(O) 465.

The assembly illustrated in FIG. 4A and FIG. 4B was modeled as anequivalent circuit consisting of two branch resistors R_(R) and R_(s)grounded by two source reservoirs (e.g., Source B 440 and Source Y 450)and terminated by outlet resistor Ro and an outlet reservoir 430. TheSource B 440 and Source Y 450 may, for example, be reservoirs of twodifferent dyes, such as blue and yellow. Each branch was designed todiffer only in resistance, specifically at the reference and selectedmodule resistance (R_(ref) 405 and R_(select) 410), while havingidentical support modules resulting in equal structural resistanceR_(struct). All resistors in the equivalent circuit model wereapproximated by series addition of their contributing elementresistances in the actual module assembly (see FIG. 3 and the “Label”column of Table 1 for subscript nomenclature):R=R _(I,750) +R _((T),750)+3R _(C,1000) +R _(L,750) +R _(SP,750) =R_(struct) +R _(ref)R _(s) =R _(I,750) +R _((T),750)+3R _(C,1000) +R _(L,750) +R _(SP,750)=R _(struct) +R _(select)R _(o) =R _((T),750) +R _(C,1000) +R _(I,750)

The module reference resistor R_(ref) 405 and variable resistorR_(select) 410 may uniquely control how much of the source fluids (e.g.,blue and yellow dye or non-oil liquid) enter the outlet T junction bythrottling the action of the pressure source differently in theirrespective branches. This may be analogous to the use of a currentdivider in electronic circuit design to deduce an unknown resistancewith respect to a known resistance. Nodal analysis was applied in theT-junction in order to calculate the pressure where the two dye streamswere combined, such that Q_(o)=Q_(y)+Q_(b). The contribution of each dyestream to the outlet streams was then computed by simple application ofPoiseuille's Law (deltaP=QR) (delta of Pressure=flow rate*hydrodynamicresistance), to each branch resistor:

$Q_{y} = {- {P\left( \frac{R}{{RR}_{s} + {R_{o}R_{s}} + {R_{o}R}} \right)}}$$Q_{b} = {- {P\left( \frac{R_{s}}{{RR}_{s} + {R_{o}R_{s}} + {R_{o}R}} \right)}}$

The volumetric mixing ratio m_(o) of dye streams combined in the outletresistor was predicted to have simple dependency on only the selected,reference, and branch structural resistances:

$m_{o} = {\frac{Q_{y}}{Q_{b}} = \frac{R_{struct} + R_{ref}}{R_{struct} + R_{select}}}$

FIG. 5 is a graph comparing a mixing ratio to a ratio of resistances atthe two branches of the gradient generator device of FIG. 4A and FIG. 4Bthat includes model data as well as experimental data, and illustrates adark-colored fluid mixing with a light-colored fluid at variousexperimental points on the graph. The mixing ratio (m₀ 520) isillustrated along the vertical axis of the graph, while the ratio ofresistances at the two branches of the gradient generator device(R_(ref)/R_(select) 510=R_(ref) 405 divided by R_(select) 410) isillustrated along the horizontal axis. As explained in the legend 500,the line of FIG. 5 depicts modeled data according to the equationsabove, while the points depict experimental results.

The various square inserts (530, 540, 550) in the figure illustratedepictions of the co-flowing streams at the T-junction 460 such that theratio of stream widths was used to find the output mixing ratio m_(o).The depiction is based on experimental results using a blue dye and ayellow dye, but herein is recolored as a dark-colored fluid and alight-colored fluid. The method of Park et al. (Choi S, Lee M G, ParkJ-K, Biomicrofluidics, 2010) was adapted to measure several mixingratios with varying R_(select) 410 and compared to theoretical valuescalculated from the equation above, validating the simple nodal modelwith good agreement between the experimental results and the model. Theresident widths of unmixed collinear dye streams were measured opticallyin the junction before diffusive mixing could occur. Assuming that thetwo dyed water streams have equal dynamic viscosity, the ratio of theirresident widths may then be directly proportional to their flow ratesand thus the resistances of their originating branches.

In particular, the graph of FIG. 5 illustrates results in which Source Y450, which is at the same branch as R_(select) 410, was filled withyellow dye (here illustrated as light-colored fluid) and Source B 440,which is at the same branch as R_(ref) 405, was filled with blue dye(here illustrated as dark-colored fluid). Higher values for R_(select)410 are illustrated as further left along the horizontal axis 510.Higher values for R_(select) 410 thus resulted in less yellow dye andmore blue dye at the output (facing left). For example, the result 550has the least yellow dye due to a higher R_(select) 410 resistancevalue, the result 530 has the most yellow dye due to a lower R_(select)410 resistance value, and the result 540 has the is in between.

With the ability to quickly modify the assembly, this circuit becomes auseful tool for generating precise mixing ratios based on a comparisonof select and reference module resistances.

FIG. 6A illustrates an example of two single-outlet subcircuits combinedto parallelize operation of a tunable mixer to yield a two-outletdevice. In particular, the two single-outlet subcircuits are bothstructured similarly to the gradient generator device of FIG. 4A andFIG. 4B. The two-outlet device of FIG. 6A includes a R_(s1) 615 and aR_(ref1) 610 at the two branches of the left-side subcircuit (mixinginput A 605 and input B 610 and outputting output flow Q_(O1) 620), anda R_(s2) 635 and a R_(ref2) 630 at the two branches of the right-sidesubcircuit (mixing input A 605 and input B 610 and outputting outputflow Q_(O2) 640).

While R_(s1) 615 is illustrated as a mixer module 340 (which may behaveas a resistor by including, for example, a narrowed and/or longerwinding channel pathway that takes longer for fluid to traverse), R_(s2)635 is instead illustrated as a straight pass module 330. A straightpass module 330 (or any other non-mixer module, such as an L-junction ora T-junction) may have an increased resistance by, for example,narrowing the module channel within the module, introducing “turning” or“winding” or “spiraling” portions of the module channel to lengthen themodule channel, or by partially occluding the module channel within themodule (e.g., by filling at least part of it with a porous solid). Theresistance of a mixer module 340 may similarly be increased withnarrowness of the channel, increasing the length of the channel asspecified above, or partially occluding the channel as specified above.Different embodiments may use a different combination of different typesof resistors.

FIG. 6B illustrates an example of three single-outlet subcircuitscombined to parallelize operation of a tunable mixer to yield athree-outlet device.

FIG. 6C illustrates an example of four single-outlet subcircuitscombined to parallelize operation of a tunable mixer to yield afour-outlet device.

As illustrated by FIG. 6A, FIG. 6B, and FIG. 6C, the operationalprinciples of the microfluidic circuit of FIG. 4A and FIG. 4B may beexpanded by using it as a module in two, three, and four outlet,large-scale tunable mixers by adding or replacing T-, X-, andXT-junctions near the reservoir inlets. In this manner, the symmetry ofthe device around a single axis through which input streams are splitmay be maintained, such that the structural resistance in each newsingle outlet sub-circuit is unchanged between configurations.

FIG. 7A illustrates the two-outlet device of FIG. 6A in symbolic circuitnotation. The symbolic circuit notation of FIG. 7A illustrates that theoutput flow Q_(O1) 620 is collected at a Collector 1 705, and that theoutput flow Q_(O2) 640 is collected at a Collector 2 710. The mechanismmay be driven by a negative displacement pump 720 connecting the twooutput flow blocks (not shown in FIG. 6A).

FIG. 7B illustrates the two-outlet device of FIG. 6B in symbolic circuitnotation.

FIG. 7C illustrates the two-outlet device of FIG. 6C in symbolic circuitnotation.

FIG. 7A, FIG. 7B, and FIG. 7C, each illustrates an example of anequivalent circuit diagram for the module assemblies illustrated in FIG.6A, FIG. 6B, and FIG. 6C, respectively. In a planar setting, thiscontrol over parallelization of operation may be impossible due to theneed for extra structural modules in order to connect these sub-circuitsto the inlets. By driving this circuit with a constant pressure source(e.g., the negative displacement pump 720 of FIG. 7A or similar negativedisplacement pumps at FIG. 7B and FIG. 7C), each sub-circuit can beanalyzed as a unit with a mixing ratio which is independently controlledby its corresponding branch resistance ratio, as seen in the equivalentcircuit diagrams in FIG. 7A, FIG. 7B, and FIG. 7C.

Configurability: Microdroplet Generation

In addition to being straightforward to analyze in terms ofelement-by-element hydrodynamics, modular microfluidic systems may offerthe advantage of simple reconfigurability. The ability to rapidlyassemble and modify two common microfluidic circuit topologies used togenerate droplets was demonstrated: T-junction and flow-focus (see ChoiS, Lee M G, Park J-K, Biomicrofluidics, 2010, hereby incorporated byreference, for a review of these methods).

FIG. 8 illustrates an example of a T-junction emulsification circuit. Inthe T-junction configuration illustrated in FIG. 8, a single syringepump (e.g., a negative displacement pump located past the output flow830) may be used to drive two dye-bearing water streams (e.g., first dyeinput 805 and second dye input 810) into the circuit where they may becombined (e.g., at the first T-junction 815), mixed (e.g., at the mixermodule 820), and emulsified (e.g., at the second T-junction 830) in acarrier (e.g., oil) stream (e.g., from carrier input 825) before beingoutput at output flow 830. The result of the T-junction emulsificationcircuit of FIG. 8, at the right flow rates, is to “cut” the aqueous flowat the second T-junction 830 so that the output flow 830 is output asdroplets of the aqueous solution instead of as a steady stream of theaqueous solution. The droplets are output in the output flow 830 alongwith the carrier, which may be oil. Example results of the T-junctionemulsification circuit of FIG. 8 are illustrated in FIG. 11A.

If the mixer module 820 has a helical channel portion, it may in somecases lose effectiveness at aqueous flow rates above 2.5 milliliters perhour (mL hr⁻¹), determining the upper bound for the aqueous phasesub-circuit operation. The carrier phase flow rate may in this case beheld constant at 1 mL hr⁻¹, while the aqueous phase flow rate may bevaried, resulting in well-defined steady-state control of droplet sizedown to sub-millimeter sizes.

FIG. 9 illustrates an example of a four-outlet T-junction emulsificationcircuit built in three dimensions. As illustrated in FIG. 9, a3-dimensional quad-outlet version of the T-junction sub-circuit (theT-junction emulsification circuit of FIG. 8) may be constructed in orderto parallelize operation for high-throughput applications.

A single aqueous input (e.g., coupled to a dye or non-oil liquidreservoir) 905 may be is located in the center of the left side of thecircuit illustrated in FIG. 9, while a single carrier input (e.g.,coupled to an oil reservoir) 910 may be located on the right side of thecircuit illustrated in FIG. 9. The four output flows may produce aqueousdroplets in an oil solution as described in relation to FIG. 8, and maybe located in a “plus symbol” configuration around the aqueous input905.

The carrier and aqueous phases may each be split into four streams withcylindrical symmetry around an inlet axis through which they areintroduced. Each new stream may radially be transported away from theaxis, and intersected with its immiscible counterpart in T-junctionsarranged around the axis. This “equal path-length distribution” methodmay be similar to that demonstrated in parallelizing operation of thetunable mixer circuit described above.

FIG. 10 illustrates an example of a flow-focus configurationemulsification circuit. The potential to produce even smaller dropletswhile leveraging the ability to construct three-dimensional systems maybe demonstrated by replacing the T-junction sub-circuit with aflow-focus sub-circuit. The input carrier stream assembly may be builtaround the aqueous phase flow axis (which may include two aqueous inputs1010) such that carrier phase (with the carrier introduced via carrierinput 1020) is as transported vertically down into an X-junction 1040where droplets are formed. The aqueous phase flow rate may be variedonce again and the carrier phase flow rate may be raised to 5 mL hr⁻¹ inorder to prevent droplet coalescence in the connector channels near theoutlet. Example results of the flow-focus configuration emulsificationcircuit of FIG. 10 are illustrated in FIG. 11B.

FIG. 11A illustrates an example of droplet length measurements, measuredalong the center axis of exit tubing, for the T-junction emulsificationcircuit of FIG. 8. The droplet length measurements are taken using aconstant carrier flow rate 1105 of 1000 microliters per hour. Thedroplet length (vertical axis 1120) visibly increases as the aqueousflow rate (horizontal axis 1110) increases. Several dark-colored aqueousdroplets are shown in light-colored carrier solutions. For example,droplet 1130, measured at an aqueous flow rate of approximately 1000milliliters per hour, is noticeable larger than droplet 1125, which wasmeasured at an aqueous flow rate of approximately 600 milliliters perhour, and which is noticeably larger than droplet 1120, which wasmeasured at an aqueous flow rate of approximately 200 milliliters perhour.

FIG. 11B illustrates an example of droplet length measurements, measuredalong the center axis of exit tubing, for the flow-focus configurationemulsification circuit of FIG. 10. The droplet length measurements aretaken using a constant carrier flow rate 1155 of 5000 microliters perhour. The droplet length (vertical axis 1165) visibly increases as theaqueous flow rate (horizontal axis 1160) increases. Several dark-coloredaqueous droplets are shown in light-colored carrier solutions. Forexample, droplet 1180, measured at an aqueous flow rate of approximately2000 milliliters per hour, is noticeable larger than droplet 1175, whichwas measured at an aqueous flow rate of approximately 1000 millilitersper hour, and which is noticeably larger than droplet 1170, which wasmeasured at an aqueous flow rate of approximately 250 milliliters perhour.

Ultimately, then, both the circuit of FIG. 8 and the circuit of FIG. 10were measured optically and shown to reliably depend on the ratio ofaqueous and carrier phase flow rates.

Versatility: In-Situ Monitoring of Micro-Droplet Generation

Active elements may be incorporated into the modular packaging describedherein by building sensors and actuators into thestereo-lithographically fabricated parts.

FIG. 12A illustrates an example of a module with a straight pass channelintersecting the bream created between a discrete near infrared (NIR)diode emitter to a phototransistor receiver. As illustrated in FIG. 12A,an off-the-shelf, near-infrared (NIR) emitter 1220 and phototransistorreceiver 1225 pair may be incorporated into a module 1200 designed fordroplet sensing. The module 1200 may be designed such that the diode1220 and phototransistor receiver 1225 fit snugly into embossed featureson the exterior of the 1200, creating a beam path that intersects astraight pass channel element 1205. The channel may carry water dropletsdispersed in a fluorocarbon oil phase formed by an upstream T-junctioncircuit, as illustrated in FIG. 12B. Such an NIR sensor could also beembedded in a different type of module, such as an L-joint 335, a mixer340, a T-junction 345, or an interface module 355. In other cases, otherelectromagnetic frequencies (e.g., radio, microwave, infrared, visiblelight, ultraviolet) may be used in a similar sensor.

FIG. 12B illustrates an example of an assembly where the near infrared(NIR) sensing module of FIG. 12A is placed downstream from a T-junctionproducing droplets that absorb the near infrared (NIR) beam as theycross its path. The droplets may be an aqueous solution 1230 in acarrier solution 1235 joining at T-junction 1240 before a measurement istaken by the phototransistor receiver 1225 of the NIR sensor module1200. The channel may carry, for example, water droplets dispersed in afluorocarbon oil phase formed by an upstream T-junction 1240 of thecircuit of FIG. 12B,

FIG. 12C illustrates an example of a periodical signal generated by theoutput of the phototransistor receiver in FIG. 12A. For example, thephototransistor receiver 1225 of the module 1200 may reach a detectionthreshold 1250 of 4.724 volts, which may indicate a particular dropletlength detected by the phototransistor receiver 1225. An exemplaryelectronic circuit whose output may correspond to the signal of FIG. 12Cis illustrated in FIG. 13.

FIG. 12D illustrates an example of droplet length measurementdistribution as determined by an near infrared (NIR) sensor and throughoptical measurements. In particular, the graph of FIG. 12D charts acount (along a vertical axis 1265) of how many droplets of a sample ofmultiple droplets, as measured by an NIR sensor 1280 (e.g., by thephototransistor receiver 1225) of a module 1200, were detected at eachof a number of various droplet lengths (along the horizontal axis 1260).These NIR counts are compared on the chart with a count (along avertical axis 1265) of how many droplets of the sample, as measured byan optical micrograph 1285, were detected at each of a number of variousdroplet lengths (along the horizontal axis 1260). The comparison (seelegend 1270) indicates that the results are similar.

FIG. 13 illustrates an example of an electrical circuit diagramdepicting the operation of the near-infrared droplet measurementelement. The voltage signal across the NPN phototransistor detector 1225biased in saturation mode may be monitored. As droplets of water crossthe beam, they may absorb the near-infrared light from the infrared(and/or near infrared) light emitting diode (LED) 1220 much more thanthe carrier oil. The resulting signal may be digitized and communicatedto a computer device by a microcontroller in order to determine thedroplet production frequency.

The length of the droplets may be deduced from the average flow velocityin the channel and half-period of the signal (i.e. the droplet residencetime in the beam), and compared directly with droplet sizes measured byoptical microscopy. The results show good agreement between the twotechniques. They suggest that, by incorporating more market-availablediscrete electronic devices into the modules, active process monitoringand feedback control systems can be implemented with ease.

Manufacturing and Post-Processing

Modifying the surface properties of the channels may be performed bycoating them with a fluoropolymer coating via a vapor-phase techniquefor modifying channels in PDMS devices in a laboratory. Such techniquesmay be used to coat an inner surface of a module channel to producedifferent surface energies, hydrophobic properties, or other effects.

For example, a surface containing a water droplet surrounded by oil onan uncoated surface may have a higher contact angle (e.g., over 90degrees and relatively flat against the surface) than water dropletsurrounded by oil on a coated surface, which may have a relatively lowcontact angle (e.g., lower than 90 degrees and jutting away from thesurface). Coating the surface of a channel may thus produce effectivemodification of the channel hydrophobicity by initiated chemical vapordeposition. Initiated chemical vapor deposition (iCVD) may be used tocoat the channels in stereo-lithographically fabricated modules withpoly(1H,1H,2H,2H-perfluorodecyl acrylate-co-ethylene glycol diacrylate),making the channel walls hydrophobic and increasing the contact angle ofa water droplet in oil (e.g., from 67.9° to 138.3°). Such a coating neednot affect the optical clarity of the photoresin material of channelsand/or modules and/or connectors.

In addition to reversible assembly techniques (e.g., the male couplingpins and female coupling ports illustrated in FIG. 1A), severalapproaches to permanently or semi-permanently coupling multiple modulesmay be used. These approaches may be mechanical, thermal, or chemical innature, and may produce varying coupling durabilities. For example, twomodules may be coupled (with or without a connector 325) usingfast-curing epoxy or silicone pipe sealant via direct application with acotton tipped applicator. A microfluidic circuit may also be potted byconnecting interface modules to breather tubes, completely immersing theassembly in PDMS, and curing it at a predetermined high temperature(e.g., approximately 30° C.) for a predetermined amount of time (e.g.,approximately 24 hours).

Thermal Sensing

A variety of sensors may be integrated in this system beyond the NIRemitter-receiver pair described above.

FIG. 14 illustrates an example of a thermal sensing module where thechannel coming in from the top surface can house an off-the-shelfthermistor diode 1405. In FIG. 14, a market-available glass beadthermistor 1405 is configured to make contact with a microfluidic flowthrough a channel 1410 and therefore measure the temperature of themicrofluidic flow. The sensor 1405 may, for example, be calibrated forflow-rate dependent behavior and is presumed to read the temperature ofthe flow within the accuracy specified by a thermistor data sheetcorresponding to the thermistor 1405.

Magnetic Actuation

FIG. 15 illustrates an example of a magnet integrated into a module. Inapplications in biochemistry, micron scale paramagnetic beads (notshown) may be introduced to different compounds (e.g., a fluid flowingthrough channel 1510) in order to provide a removable substrate forsurface chemistries to occur. In other words, the magnetic beads can beintroduced to different reagents and withdrawn using a magnet 1505(e.g., a permanent magnet or an electromagnet). In this system, magneticbeads in microfluidic flows can be actuated to transfer from one reagentto another in a module with a local magnet or electromagnet, as shown inFIG. 15. This may be used to detect a particular compound within a fluidby introducing the reagent to magnetic beads, removing the beads after afluid has passed through channel 1510, and detecting reactions from thereagents after removal of the magnetic beads.

Valve Actuation

FIG. 16 illustrates an example of a module with an integrated valveunit. Controlling fluid flows may be accomplished through specializedmodules of the integrated valve unit 1605 with micro-solenoid valvesintegrated directly into the module framework, as shown in FIG. 16.

Further Examples

A robust solution for the rapid bench-top assembly of three-dimensionalmicrofluidic systems from a library of standardized discrete elements isdescribed herein. Modules may be fabricated using additive manufacturingmethods and characterized by their terminal flow characteristics. Thismay enable the use of circuit theory to accurately predict the operationof a microfluidic mixing system with scalable complexity in threedimensions. The assembly time (from part selection to initial testing)for a complex system can be less than one hour. In addition to beingmuch faster to prototype than monolithic devices, this system may alsoallow for three-dimensional configurations which were not previouslypossible using older technologies.

By discretizing and standardizing the primitive elements comprising suchsystems, newly found design complexity may naturally allow forhierarchal system analysis techniques borrowed from the hydraulicanalogy to electronic circuit design. In turn, this may allow thedesigner to focus more on satisfying a dynamic set of operational loadrequirements, rather than working within the restrictively staticenvironment of planar manufacturing.

The ability to reconfigure these systems towards expanded operationalcapabilities may be further demonstrated by attaching threeemulsification sub-circuit modules to a simple mixing circuit in orderto form droplets over a wide range of volumes and generation rates.Despite less need for analytically predictable operation, piecewisevalidation may also be shown for these canonical two-phase flow systemsby qualifying the mixer sub-circuits and then in turn the emulsifiersub-circuits for functionality. In a monolithic device, each of thecircuits demonstrated may comprise a single system prone to completefailure due to singular manufacturing error or design error of a singleelement. In the systems described in this disclosure, modules in circuitassembly may be quickly assessed for their independent contribution tofailure and replaced or modified accordingly. After successful test andvalidation, the devices may optionally be sealed into permanentconfigurations while maintaining their optical clarity and ease ofinterfacing.

The operational performance of one of these circuits may be monitored byincluding a single active module capable of performing in-situ sensing.The ability to reconfigure this system may thus also be advantageousfrom the standpoint of metering systems before finalization of a design.In addition, the inclusion of active sensing modules may be particularlyadvantageous when considering process monitoring in highly complexsystems with many sub-circuits: densely routed microfluidic systems maynot integrate well into standard analysis tools such as opticalmicroscopes.

The modules and channels described herein, and the arrangements that canbe made using them, can make discrete microfluidics a valuabledevelopment vehicle for a complex design that has not yet been achieved.With a wider library of passive and active modules to choose from, thissystem can replace monolithically integrated devices for manymicrofluidic applications. In addition, this system may benefitimmensely as industrial additive manufacturing technologies alsoimprove, allowing for the further miniaturization of elements anddevelopment of an even larger selection of elements and materials.

FIG. 17A illustrates an internal view of an exemplary optical sensormodule where an LED is housed on the top surface of the module and asensor is housed on the bottom surface of the module.

FIG. 17B illustrates an opaque external view of the exemplary opticalsensor module of FIG. 17A.

FIG. 18 illustrates an example of a mixer module with a visible openingon the front left side and a non-visible opening on the right-back side,and a visual indicator on the top surface.

FIG. 19 illustrates an example of a straight-pass module with twoopenings at the top and at the bottom, and with a visual indicatorpresent on several side surfaces of the module.

The modules, steps, features, objects, benefits, and advantages thathave been discussed are merely illustrative. None of them, nor thediscussions relating to them, are intended to limit the scope ofprotection in any way. Numerous other embodiments are also contemplated.These include embodiments that have fewer, additional, and/or differentmodules, steps, features, objects, benefits, and/or advantages. Thesealso include embodiments in which the modules and/or steps are arrangedand/or ordered differently.

Unless otherwise stated, all measurements, values, ratings, positions,magnitudes, sizes, and other specifications that are set forth in thisspecification, including in the claims that follow, are approximate, notexact. They are intended to have a reasonable range that is consistentwith the functions to which they relate and with what is customary inthe art to which they pertain.

All articles, patents, patent applications, and other publications thathave been cited in this disclosure are incorporated herein by reference.

The phrase “means for” when used in a claim is intended to and should beinterpreted to embrace the corresponding structures and materials thathave been described and their equivalents. Similarly, the phrase “stepfor” when used in a claim is intended to and should be interpreted toembrace the corresponding acts that have been described and theirequivalents. The absence of these phrases from a claim means that theclaim is not intended to and should not be interpreted to be limited tothese corresponding structures, materials, or acts, or to theirequivalents.

The scope of protection is limited solely by the claims that now follow.That scope is intended and should be interpreted to be as broad as isconsistent with the ordinary meaning of the language that is used in theclaims when interpreted in light of this specification and theprosecution history that follows, except where specific meanings havebeen set forth, and to encompass all structural and functionalequivalents.

Relational terms such as “first” and “second” and the like may be usedsolely to distinguish one entity or action from another, withoutnecessarily requiring or implying any actual relationship or orderbetween them. The terms “comprises,” “comprising,” and any othervariation thereof when used in connection with a list of elements in thespecification or claims are intended to indicate that the list is notexclusive and that other elements may be included. Similarly, an elementpreceded by an “a” or an “an” does not, without further constraints,preclude the existence of additional elements of the identical type.

None of the claims are intended to embrace subject matter that fails tosatisfy the requirement of Sections 101, 102, or 103 of the Patent Act,nor should they be interpreted in such a way. Any unintended coverage ofsuch subject matter is hereby disclaimed. Except as just stated in thisparagraph, nothing that has been stated or illustrated is intended orshould be interpreted to cause a dedication of any module, step,feature, object, benefit, advantage, or equivalent to the public,regardless of whether it is or is not recited in the claims.

The abstract is provided to help the reader quickly ascertain the natureof the technical disclosure. It is submitted with the understanding thatit will not be used to interpret or limit the scope or meaning of theclaims. In addition, various features in the foregoing detaileddescription are grouped together in various embodiments to streamlinethe disclosure. This method of disclosure should not be interpreted asrequiring claimed embodiments to require more features than areexpressly recited in each claim. Rather, as the following claimsreflect, inventive subject matter lies in less than all features of asingle disclosed embodiment. Thus, the following claims are herebyincorporated into the detailed description, with each claim standing onits own as separately claimed subject matter.

The invention claimed is:
 1. A system for modular fluid handling, thesystem comprising: a first module of a first three-dimensionalpolyhedral shape, the first module comprising a material and having anexterior with four or more faces; a first opening on a first face of thefour or more faces of the first module, wherein the first face is of afirst polygonal shape; a second opening on a second face of the four ormore faces of the first module, wherein the second face is of the firstpolygonal shape; a microfluidic channel passing through at least part ofthe first module and passing a fluid between at least the first openingand the second opening; a light emitter embedded into the first module,wherein the light emitter emits light that intersects with themicrofluidic channel while the microfluidic channel passes the fluid; areceiver embedded into the first module, wherein the receiver receivesthe light emitted by the light emitter that intersects with themicrofluidic channel, wherein a voltage signal from the receiver isindicative of a parameter of the fluid while the receiver receives thelight that intersects with the microfluidic channel; a first couplingmechanism on the first face of the first module, wherein the firstmodule is connected to a second module of the first three-dimensionalpolyhedral shape via a first connector, the first coupling mechanismsecuring the first connector to the first face of the first module andallowing fluid flow between the first opening and the second modulethrough the first connector; and a second coupling mechanism on thesecond face of the first module, wherein the first module is connectedto a third module of the first three-dimensional polyhedral shape via asecond connector, the second coupling mechanism securing the secondconnector to the second face of the first module and allowing fluid flowbetween the second opening and the third module through the secondconnector, wherein the fluid flows along at least one microfluidic flowpath through each module and each connector of an assembly constructedusing a plurality of modules and a plurality of connectors, theplurality of modules including at least the first module and the secondmodule and the third module, the plurality of connectors including atleast the first connector and the second connector, wherein theplurality of modules of the assembly are tiled in three dimensionswithin a three-dimensional regular polyhedral grid.
 2. The system ofclaim 1, further comprising: a microcontroller that identifies that thevoltage signal from the receiver has reached at least a detectionthreshold voltage, indicating that a droplet of the fluid is of at leasta particular length.
 3. The system of claim 1, wherein thethree-dimensional polyhedral grid is based on the firstthree-dimensional polyhedral shape, and wherein a subset of theplurality of modules of the assembly are secured in a polyhedralprimitive cell arrangement based on the first three-dimensionalpolyhedral shape in which one of the subset of the plurality of modulesis positioned at each corner of the polyhedral primitive cellarrangement.
 4. The system of claim 1, wherein the receiver is aphototransistor.
 5. The system of claim 1, wherein the parameter of thefluid is a length of a droplet of the fluid.
 6. The system of claim 1,wherein the plurality of modules includes a magnet module having amagnet embedded therein that withdraws a magnetic bead from the fluid,wherein the magnetic bead is a substrate to a reagent.
 7. The system ofclaim 1, further comprising a coating applied along an interior surfaceof the microfluidic channel via initiated chemical vapor deposition,wherein the coating modifies hydrophobicity of the interior surface ofthe microfluidic channel.
 8. The system of claim 1, further comprising amicrocontroller that digitizes the voltage signal from the receiver. 9.The system of claim 1, wherein a surface of the microfluidic channelincludes a surface material that reacts with one or more chemicals inthe fluid flowing through the microfluidic channel.
 10. The system ofclaim 1, wherein the light that is emitted by the light emitter andreceived by the receiver is of one or more electromagnetic frequencies,wherein the one or more electromagnetic frequencies include at least oneof an infrared (IR) frequency or a near-infrared (NIR) frequency. 11.The system of claim 1, wherein the parameter of the fluid is a dropletfrequency of the fluid.
 12. The system of claim 1, wherein the lightemitter and the receiver are embedded into a stereo-lithographicallyfabricated part of the first module.
 13. The system of claim 1, whereinthe light emitter is embedded into one or more embossed features on athird face of the four or more faces of the first module, and whereinthe receiver is embedded into one or more embossed features on a fourthface of the four or more faces of the first module.
 14. A system formodular fluid handling, the system comprising: a plurality of modules,wherein each module of the plurality of modules is of a firstthree-dimensional polyhedral shape, wherein each module of the pluralityof modules comprises a material through which a microfluidic channelpasses and carries fluid between a plurality of openings that are eachon different faces of an exterior of the module, wherein one of theplurality of modules is an optical sensor module, a light emitter and areceiver embedded into the optical sensor module, wherein the lightemitter emits light that passes through the microfluidic channel of theoptical sensor module at least while the microfluidic channel of theoptical sensor module carries the fluid, wherein the receiver receivesthe light and outputs a voltage signal that is indicative of a parameterof the fluid; and a plurality of connectors, wherein each connector ofthe plurality of connectors includes a second microfluidic channel,wherein each module of the plurality of modules is connected to at leastone other module of the plurality of modules via one of the plurality ofconnectors so that the plurality of modules and the plurality ofconnectors are connected together into an assembly having at least onemicrofluidic flow path conveying the fluid through each module and eachconnector of the assembly, wherein the plurality of modules of theassembly are tiled in three dimensions within a three-dimensionalpolyhedral grid.
 15. The system of claim 14, wherein the plurality ofmodules includes a thermal sensor module having a thermistor embeddedtherein, wherein the thermistor is in contact with the microfluidicchannel of the thermal sensor module.
 16. The system of claim 14,wherein at least a subset of the plurality of modules modulate aconcentration of an ingredient within the fluid to a predeterminedconcentration.
 17. The system of claim 14, wherein the plurality ofmodules of the assembly include at least one three-dimensionalpolyhedral primitive cell arrangement of modules.
 18. A method ofmodular fluid handling, the method comprising: receiving a fluid into amicrofluidic flow path comprising a plurality of microfluidic channelsthat are connected to each other, wherein a first subset of theplurality of microfluidic channels are within a plurality of modules,wherein a remainder of the plurality of microfluidic channels other thanthe first subset are found in a plurality of connectors, wherein eachmodule of the plurality of modules is of a first three-dimensionalpolyhedral shape, wherein each connector of the plurality of connectorsis of a second shape, wherein each module of the plurality of modules isconnected to at least one other module of the plurality of modules viaone of the plurality of connectors so that the plurality of modules andthe plurality of connectors are connected together into an assembly, themicrofluidic flow path conveying the fluid through each module and eachconnector of the assembly, wherein the plurality of modules of theassembly are tiled in three dimensions within a three-dimensionalpolyhedral grid; receiving the fluid into a first opening of themicrofluidic channel of an optical sensor module of the plurality ofmodules while the fluid traverses the microfluidic flow path; passingthe fluid through the microfluidic channel of the optical sensor moduleto a second opening of the microfluidic channel of the optical sensormodule; emitting light from a light emitter embedded into the opticalsensor module so that the light intersects with the microfluidic channelof the optical sensor module while the fluid passes through themicrofluidic channel of the optical sensor module; receiving the lightvia a receiver embedded into the optical sensor module; and outputting avoltage signal from the receiver in response to receiving the light viathe receiver, wherein the voltage signal is indicative of a parameter ofthe fluid.
 19. The method of claim 18, further comprising: generating adigitized signal via a microcontroller associated with the first moduleby digitizing the voltage signal from the receiver; and transmitting thedigitized signal from the microcontroller to a computing device, therebyconveying the parameter of the fluid to the computing device.
 20. Themethod of claim 18, wherein the fluid is passed through the plurality ofmicrofluidic channels on a scale of nano-liters or smaller, and furtherwherein flow of the fluid is laminar during passage of the fluid throughat least a subset of the plurality of microfluidic channels.
 21. Thesystem of claim 1, wherein each connector of the plurality of connectorsincludes a first coupling module that secures to a coupling mechanism ofone of the plurality of modules, a second coupling module that securesto a coupling mechanism of another of the plurality of modules, a spacerarranged between the first and second coupling modules and a connectorchannel passing the fluid between an opening along the first couplingmodule and an opening along the second coupling module.